Kevin William Hoffman, MD, PhD

All Publications

• Exposomic and polygenic contributions to allostatic load in early adolescence NATURE MENTAL HEALTH Hoffman, K. W., Tran, K. T., Moore, T. M., Gatavins, M. M., Visoki, E., Kwon, O., Didomenico, G. E., Chaiyachati, B. H., Schultz, L. M., Almasy, L., Hayes, M. R., Daskalakis, N. P., Barzilay, R. 2024; 2 (7)

  View details for DOI 10.1038/s44220-024-00255-9

  View details for Web of Science ID 001390107400005

• Association between Asthma and Suicidality in 9-12-Year-Old Youths. Brain sciences Hoffman, K. W., Visoki, E., Argabright, S. T., Schultz, L. M., Didomenico, G. E., Tran, K. T., Gordon, J. H., Chaiyachati, B. H., Moore, T. M., Almasy, L., Barzilay, R. 2022; 12 (12)

  Abstract

  Suicidal ideation and attempts in youth are a growing health concern, and more data are needed regarding their biological underpinnings. Asthma is a common chronic inflammatory disorder in youth and has been associated with suicidal ideation and attempts in adolescent and adult populations, but data in younger children and early adolescents are lacking. We wished to study associations of asthma with childhood suicidality considering asthma's potential as a clinically relevant model for childhood chronic immune dysregulation.Using data from the Adolescent Brain Cognitive Development (ABCD) Study (n = 11,876, 47.8% female, mean age 9.9 years at baseline assessment and 12.0 years at two-year follow-up), we assessed associations between asthma and suicidal ideation and attempts through baseline to two-year follow-up.Asthma history as defined by parent report (n = 2282, 19.2% of study population) was associated with suicide attempts (SA) (odds ratio (OR) = 1.44, p = 0.01), and this association remained significant even when controlling for demographics, socioeconomic factors, and environmental factors (OR = 1.46, p = 0.028). History of asthma attacks was associated with both suicidal ideation (SI) and SA when controlling for demographics, socioeconomic factors, and environmental factors (OR = 1.27, p = 0.042; OR = 1.83, p = 0.004, respectively). The association of asthma attack with SA remained significant when controlling for self-reported psychopathology (OR = 1.92, p = 0.004). The total number of asthma attacks was associated with both SI and SA (OR = 1.03, p = 0.043; OR = 1.06, p = 0.05, respectively).Findings suggest an association between asthma and suicidality in early adolescence. Further research is needed to investigate mechanisms underlying this relationship.

  View details for DOI 10.3390/brainsci12121602

  View details for PubMedID 36552062

  View details for PubMedCentralID PMC9775696

• Considering the Microbiome in Stress-Related and Neurodevelopmental Trajectories to Schizophrenia. Frontiers in psychiatry Hoffman, K. W., Lee, J. J., Corcoran, C. M., Kimhy, D., Kranz, T. M., Malaspina, D. 2020; 11: 629

  Abstract

  Early life adversity and prenatal stress are consistently associated with an increased risk for schizophrenia, although the exact pathogenic mechanisms linking the exposures with the disease remain elusive. Our previous view of the HPA stress axis as an elegant but simple negative feedback loop, orchestrating adaptation to stressors among the hypothalamus, pituitary, and adrenal glands, needs to be updated. Research in the last two decades shows that important bidirectional signaling between the HPA axis and intestinal mucosa modulates brain function and neurochemistry, including effects on glucocorticoid hormones and brain-derived neurotrophic factor (BDNF). The intestinal microbiome in earliest life, which is seeded by the vaginal microbiome during delivery, programs the development of the HPA axis in a critical developmental window, determining stress sensitivity and HPA function as well as immune system development. The crosstalk between the HPA and the Microbiome Gut Brain Axis (MGBA) is particularly high in the hippocampus, the most consistently disrupted neural region in persons with schizophrenia. Animal models suggest that the MGBA remains influential on behavior and physiology across developmental stages, including the perinatal window, early childhood, adolescence, and young adulthood. Understanding the role of the microbiome on critical risk related stressors may enhance or transform of understanding of the origins of schizophrenia and offer new approaches to increase resilience against stress effects for preventing and treating schizophrenia.

  View details for DOI 10.3389/fpsyt.2020.00629

  View details for PubMedID 32719625

  View details for PubMedCentralID PMC7350783

• Adolescent Depressive Symptom Trajectories From Before to After the COVID-19 Pandemic. JAMA network open Gatavinš, M. M., Tran, K. T., Visoki, E., Moore, T. M., Hoffman, K. W., Shilton, T., Schultz, L. M., Almasy, L., Mancini, A. D., Barzilay, R. 2025; 8 (12): e2545987

  Abstract

  Adolescent depression rates increased during the COVID-19 pandemic globally. Data on risk and resilience factors can inform prevention and intervention strategies during a major adversity.To characterize depression symptom trajectories from before, during, and after the lockdown stages of the pandemic and to identify prospective risk and resilience factors.This cohort study followed participants from the Adolescent Brain Cognitive Development Study ascertained through 21 sites across the US from before March 2020 to February 2022. The design and hypotheses were preregistered in March 2024. Analyses were conducted from April to November 2024.Prepandemic risk and resilience factors spanning developmental stage, household environment, peer relationships, and depression polygenic risk.The primary outcome was depression-susceptible symptom trajectory of low prepandemic and high postpandemic symptoms. Trajectories of depression symptom score (6 symptoms: depressed mood, anhedonia, guilt or worthlessness, fatigue, sleep, and concentration impairments) were modeled using logistic regression models with prepandemic factors (independent variables) explaining trajectory class (dependent variable; resilient, 0; depression susceptible, 1), adjusting for sex and age at the pandemic onset.In the sample of 3512 participants included in the analyses (mean [SD] age in March 2020, 12.05 [0.85] years; 1672 [47.6%] female), a 3-class trajectory model identified resilient (low symptoms throughout follow-up, 3027 participants [86.2%]), depression-susceptible (low symptoms before the pandemic and high symptoms after the pandemic, 326 participants [9.3%]), and chronically high (159 participants [4.5%]) symptom trajectory classes. Girls were overrepresented in the depression-susceptible vs the resilient group (240 girls [73.6%] vs 1327 girls [43.8%]). The depression-susceptible trajectory, compared with the resilient trajectory, was associated with late pubertal or postpubertal stage before the pandemic (odds ratio [OR], 1.46; 95% CI, 1.08-1.96; P = .01), prepandemic family conflict (OR, 1.23; 95% CI, 1.10-1.38; P < .001), peer bullying (OR, 1.71; 95% CI, 1.11-2.65; P = .02), cyberbullying (OR, 2.28; 95% CI, 1.45-3.59; P < .001), maternal history of depression (OR, 1.52; 95% CI, 1.16-1.99; P = .002), polyenvironmental adversity exposure (OR, 1.28; 95% CI, 1.13-1.45; P < .001), and polygenic risk of depression (OR, 1.28; 95% CI, 1.03-1.59; P = .02 among those of European-like genetic ancestry, but not those of African-like ancestry). Greater prepandemic parental monitoring (OR, 0.81; 95% CI, 0.73-0.91; P < .001) and problem-solving skills (OR, 0.80; 95% CI, 0.66-0.97; P = .02) were associated with lower depression susceptibility.In this cohort study of adolescent depression trajectories throughout COVID-19, girls, teens in later puberty, and those with experiences of peer bullying, cyberbullying, and greater family conflict before the pandemic were more susceptible to developing depressive symptoms that persisted after the pandemic, whereas prepandemic parental monitoring and problem-solving skills were identified as prospective modifiable resilience factors.

  View details for DOI 10.1001/jamanetworkopen.2025.45987

  View details for PubMedID 41324960

  View details for PubMedCentralID PMC12670201

• Association Between Extreme Heat and Externalizing Symptoms in Pre- and Early Adolescence: Findings From the ABCD Study. JAACAP open Briker, S., Tran, K. T., Visoki, E., Gordon, J. H., Hoffman, K. W., Barzilay, R. 2025; 3 (3): 713-724

  Abstract

  Considering the growing threat of climate change and the current youth mental health crisis, data are needed on the relationship between climate and youth mental health. Hot weather contributes to the mental health burden, specifically aggression. We studied associations between extreme heat and externalizing symptoms or suicidal behavior among US preadolescents.We analyzed data from the Adolescent Brain Cognitive Development (ABCD) Study. Participants (N = 8,120, mean age 9.89 years at baseline, 48.40% female, 23.81% Black, 18.17% Hispanic) were assessed longitudinally between 2016 and 2020 across 21 sites. We estimated exposure to extreme heat (measured around the study site) as the number of days in the month of study visit with a maximum temperature ≥90°F (32.2°C) based on National Centers for Environmental Information data. We characterized exposure to extreme heat across racial/ethnic groups. We used mixed-effects regression models to test associations of extreme heat with externalizing symptoms (parent-report) and suicide attempts (self-report), assessed in a validated clinical interview. Models adjusted for demographics (age, sex, race, ethnicity, and household income) and neighborhood characteristics (gross residential density, population density, national walkability index, and fraction of grass, forest, and built land use).Exposure to extreme heat was less prevalent among non-Hispanic White participants (5.2 days/mo) compared to non-Hispanic Black and to Hispanic youth (7.2 and 7.4 days/mo, respectively). Extreme heat showed a small but significant association with externalizing symptoms (incidence rate ratio [IRR]=1.06, 95% CI = 1.04-1.08, p < .001). The association did not change when adjusting for demographics, and remained similar when further adjusting for neighborhood characteristics (IRR = 1.05, 95% CI = 1.00-1.12, p = .04). Sensitivity analyses using extreme heat at the participants' home address level in the 6 days prior to study visit, available only for ABCD baseline assessment, revealed similar findings. Extreme heat was not associated with suicide attempts (odds ratio = 0.94, 95% CI = 0.77-1.14, p = .52).Our findings add to the literature on the association between extreme heat and externalizing symptoms, and suggest that this association already exists in preadolescence. Future studies are warranted to better understand the mechanisms linking hot weather and mental health and its related racial/ethnic disparities.Association between extreme heat and mental health in early adolescence; https://osf.io/ph7y2/.We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote sex and gender balance in our author group.We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list.

  View details for DOI 10.1016/j.jaacop.2024.09.009

  View details for PubMedID 40922773

  View details for PubMedCentralID PMC12414308

• The Role of Individual Discrimination and Structural Stigma in the Mental Health of Sexual Minority Youth. Journal of the American Academy of Child and Adolescent Psychiatry Gordon, J. H., Tran, K. T., Visoki, E., Argabright, S. T., DiDomenico, G. E., Saiegh, E., Hoffman, K. W., Erez, G., Barzilay, R. 2024; 63 (2): 231-244

  Abstract

  Sexual minority (SM) youth experience a greater mental health burden compared with their heterosexual peers. This study aimed to characterize mental health disparities among SM compared with non-SM youth, test main and interactive associations of SM identity and stressors targeting SM youth at the individual level (interpersonal SM discrimination) and structural level (state-level structural SM stigma) with youth mental health, and explore the contribution of interpersonal SM discrimination to the mental health burden of SM youth.Participants included 11,622 youth (ages 9-13; 47.6% assigned female at birth) from the Adolescent Brain Cognitive Development (ABCD) Study. Linear mixed-effects models tested main and interactive associations of SM identity, interpersonal SM discrimination, and structural SM stigma with mental health measures (self-reported overall psychopathology, suicidal ideation, and suicide attempts), adjusting for demographics and other interpersonal stressors not specific to SM (other discrimination types, peer victimization, and cyberbullying). Longitudinal mediation models tested whether interpersonal SM discrimination mediated the associations between SM identity and mental health measures.SM youth (n = 1,051) experienced more interpersonal SM discrimination and overall psychopathology compared with their non-SM peers (n = 10,571). Adjusting for demographics, there were significant associations (main effects) of interpersonal SM discrimination and structural SM stigma with overall psychopathology. When further adjusting for other non-SM-related stressors, the main effect of structural SM stigma was no longer significant. Interpersonal SM discrimination was also significantly associated with suicidal ideation and attempt, accounting for demographics, while structural SM stigma was not. Accounting for both demographics and other non-SM stressors, there was a significant interaction between SM identity and structural SM stigma in association with psychopathology (p = .02), such that, compared with their peers, SM youth showed a greater association between structural SM stigma and psychopathology. Longitudinal mediation revealed that interpersonal SM discrimination was a significant mediator explaining approximately 10% to 15% of the variance of the pathways between SM identity and all mental health outcomes.Results delineate contributions of interpersonal discrimination and structural stigma targeting SM youth to their heightened mental health burden in early adolescence. These findings underscore the need to address microlevel and macrolevel SM discrimination and structural stigma when caring for this population.We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote sex and gender balance in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list.

  View details for DOI 10.1016/j.jaac.2023.05.033

  View details for PubMedID 37422106

  View details for PubMedCentralID PMC10770287

• Methadone Dosing for Opioid Use Disorder in the Setting of Infective Endocarditis and QTc Prolongation. Journal of the Academy of Consultation-Liaison Psychiatry Todaro, D. R., Hoffman, K. W., Zwiebel, S. J. 2023; 64 (6): 583-584

  View details for DOI 10.1016/j.jaclp.2023.05.002

  View details for PubMedID 38065657

• Gut and oral microbiome modulate molecular and clinical markers of schizophrenia-related symptoms: A transdiagnostic, multilevel pilot study. Psychiatry research Lee, J. J., Piras, E., Tamburini, S., Bu, K., Wallach, D. S., Remsen, B., Cantor, A., Kong, J., Goetz, D., Hoffman, K. W., Bonner, M., Joe, P., Mueller, B. R., Robinson-Papp, J., Lotan, E., Gonen, O., Malaspina, D., Clemente, J. C. 2023; 326: 115279

  Abstract

  Although increasing evidence links microbial dysbiosis with the risk for psychiatric symptoms through the microbiome-gut-brain axis (MGBA), the specific mechanisms remain poorly characterized. In a diagnostically heterogeneous group of treated psychiatric cases and nonpsychiatric controls, we characterized the gut and oral microbiome, plasma cytokines, and hippocampal inflammatory processes via proton magnetic resonance spectroscopic imaging (1H-MRSI). Using a transdiagnostic approach, these data were examined in association with schizophrenia-related symptoms measured by the Positive and Negative Syndrome Scale (PANSS). Psychiatric cases had significantly greater heterogeneity of gut alpha diversity and an enrichment of pathogenic taxa, like Veillonella and Prevotella, in the oral microbiome, which was an accurate classifier of phenotype. Cases exhibited significantly greater positive, negative, and general PANSS scores that uniquely correlated with bacterial taxa. Strong, positive correlations of bacterial taxa were also found with cytokines and hippocampal gliosis, dysmyelination, and excitatory neurotransmission. This pilot study supports the hypothesis that the MGBA influences psychiatric symptomatology in a transdiagnostic manner. The relative importance of the oral microbiome in peripheral and hippocampal inflammatory pathways was highlighted, suggesting opportunities for probiotics and oral health to diagnose and treat psychiatric conditions.

  View details for DOI 10.1016/j.psychres.2023.115279

  View details for PubMedID 37331068

  View details for PubMedCentralID PMC10595250

• Exploring the intersection of the microbiome and the developing brain: Impacts on schizophrenia risk. Schizophrenia research Gupta, L., Hoffman, K. W. 2022; 247: 92-100

  Abstract

  Recent findings show that the perinatal maternal and infant microbiomes have profound potential to impact long term health outcomes. Of particular interest are the ways in which the microbiome influences the developing brain during one of its most critical windows. Schizophrenia and psychosis risk are strongly connected to disruptions in perinatal neurodevelopment. In this review we present an overview of critical aspects in development of both the microbiome and brain, discuss their overlap, and consider what role the microbiome plays in schizophrenia risk during the perinatal window. Considering this, we discuss ways in which expecting and new mothers may reduce offspring schizophrenia risk.

  View details for DOI 10.1016/j.schres.2021.08.010

  View details for PubMedID 34483026

• Aberrant type 1 immunity drives susceptibility to mucosal fungal infections. Science (New York, N.Y.) Break, T. J., Oikonomou, V., Dutzan, N., Desai, J. V., Swidergall, M., Freiwald, T., Chauss, D., Harrison, O. J., Alejo, J., Williams, D. W., Pittaluga, S., Lee, C. R., Bouladoux, N., Swamydas, M., Hoffman, K. W., Greenwell-Wild, T., Bruno, V. M., Rosen, L. B., Lwin, W., Renteria, A., Pontejo, S. M., Shannon, J. P., Myles, I. A., Olbrich, P., Ferré, E. M., Schmitt, M., Martin, D., Barber, D. L., Solis, N. V., Notarangelo, L. D., Serreze, D. V., Matsumoto, M., Hickman, H. D., Murphy, P. M., Anderson, M. S., Lim, J. K., Holland, S. M., Filler, S. G., Afzali, B., Belkaid, Y., Moutsopoulos, N. M., Lionakis, M. S. 2021; 371 (6526)

  Abstract

  Human monogenic disorders have revealed the critical contribution of type 17 responses in mucosal fungal surveillance. We unexpectedly found that in certain settings, enhanced type 1 immunity rather than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with AIRE deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon-γ (IFN-γ)- and signal transducer and activator of transcription 1 (STAT1)-dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN-γ or Janus kinase (JAK)-STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T cell-dependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans.

  View details for DOI 10.1126/science.aay5731

  View details for PubMedID 33446526

  View details for PubMedCentralID PMC8326743

• Hippocampal metabolite concentrations in schizophrenia vary in association with rare gene variants in the TRIO gene. Schizophrenia research Malaspina, D., Gonen, O., Rhodes, H., Hoffman, K. W., Heguy, A., Walsh-Messinger, J., Chao, M. V., Kranz, T. M. 2020; 224: 167-169

  View details for DOI 10.1016/j.schres.2020.11.001

  View details for PubMedID 33183947

• Lymphocyte-driven regional immunopathology in pneumonitis caused by impaired central immune tolerance. Science translational medicine Ferré, E. M., Break, T. J., Burbelo, P. D., Allgäuer, M., Kleiner, D. E., Jin, D., Xu, Z., Folio, L. R., Mollura, D. J., Swamydas, M., Gu, W., Hunsberger, S., Lee, C. R., Bondici, A., Hoffman, K. W., Lim, J. K., Dobbs, K., Niemela, J. E., Fleisher, T. A., Hsu, A. P., Snow, L. N., Darnell, D. N., Ojaimi, S., Cooper, M. A., Bozzola, M., Kleiner, G. I., Martinez, J. C., Deterding, R. R., Kuhns, D. B., Heller, T., Winer, K. K., Rajan, A., Holland, S. M., Notarangelo, L. D., Fennelly, K. P., Olivier, K. N., Lionakis, M. S. 2019; 11 (495)

  Abstract

  Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic disorder caused by AIRE mutations, presents with several autoimmune diseases. Among these, endocrine organ failure is widely recognized, but the prevalence, immunopathogenesis, and treatment of non-endocrine manifestations such as pneumonitis remain poorly characterized. We enrolled 50 patients with APECED in a prospective observational study and comprehensively examined their clinical and radiographic findings, performed pulmonary function tests, and analyzed immunological characteristics in blood, bronchoalveolar lavage fluid, and endobronchial and lung biopsies. Pneumonitis was found in >40% of our patients, presented early in life, was misdiagnosed despite chronic respiratory symptoms and accompanying radiographic and pulmonary function abnormalities, and caused hypoxemic respiratory failure and death. Autoantibodies against BPIFB1 and KCNRG and the homozygous c.967_979del13 AIRE mutation are associated with pneumonitis development. APECED pneumonitis features compartmentalized immunopathology, with accumulation of activated neutrophils in the airways and lymphocytic infiltration in intraepithelial, submucosal, peribronchiolar, and interstitial areas. Beyond APECED, we extend these observations to lung disease seen in other conditions with secondary AIRE deficiency (thymoma and RAG deficiency). Aire-deficient mice had similar compartmentalized cellular immune responses in the airways and lung tissue, which was ameliorated by deficiency of T and B lymphocytes. Accordingly, T and B lymphocyte-directed immunomodulation controlled symptoms and radiographic abnormalities and improved pulmonary function in patients with APECED pneumonitis. Collectively, our findings unveil lung autoimmunity as a common, early, and unrecognized manifestation of APECED and provide insights into the immunopathogenesis and treatment of pulmonary autoimmunity associated with impaired central immune tolerance.

  View details for DOI 10.1126/scitranslmed.aav5597

  View details for PubMedID 31167928

  View details for PubMedCentralID PMC6647037

• Dengue Virus Immunity Increases Zika Virus-Induced Damage during Pregnancy. Immunity Brown, J. A., Singh, G., Acklin, J. A., Lee, S., Duehr, J. E., Chokola, A. N., Frere, J. J., Hoffman, K. W., Foster, G. A., Krysztof, D., Cadagan, R., Jacobs, A. R., Stramer, S. L., Krammer, F., García-Sastre, A., Lim, J. K. 2019; 50 (3): 751-762.e5

  Abstract

  Zika virus (ZIKV) has recently been associated with birth defects and pregnancy loss after maternal infection. Because dengue virus (DENV) and ZIKV co-circulate, understanding the role of antibody-dependent enhancement in the context of pregnancy is critical. Here, we showed that the presence of DENV-specific antibodies in ZIKV-infected pregnant mice significantly increased placental damage, fetal growth restriction, and fetal resorption. This was associated with enhanced viral replication in the placenta that coincided with an increased frequency of infected trophoblasts. ZIKV-infected human placental tissues also showed increased replication in the presence of DENV antibodies, which was reversed by FcγR blocking antibodies. Furthermore, ZIKV-mediated fetal pathogenesis was enhanced in mice in the presence of a DENV-reactive monoclonal antibody, but not in the presence of the LALA variant, indicating a dependence on FcγR engagement. Our data suggest a possible mechanism for the recent increase in severe pregnancy outcomes after ZIKV infection in DENV-endemic areas.

  View details for DOI 10.1016/j.immuni.2019.01.005

  View details for PubMedID 30737148

  View details for PubMedCentralID PMC6947917

• Sex differences in cytokine production following West Nile virus infection: Implications for symptom manifestation. Pathogens and disease Hoffman, K. W., Lee, J. J., Foster, G. A., Krysztof, D., Stramer, S. L., Lim, J. K. 2019; 77 (2)

  Abstract

  West Nile virus (WNV) infection outcomes vary among individuals, with most infections resulting in asymptomatic or mild flu-like symptoms. We previously reported an association between early cytokine production and symptom outcome following WNV infection in US blood donors. In this meta-analysis, we found that WNV-infected females reported more symptoms than WNV-infected males, despite similar initial viremia and type I interferon responses. As the infection progressed, males exhibited a protracted cytokine response-marked by sustained CCL2 (MCP-1), CCL11 (eotaxin-1), CXCL10 (IP-10) and IL-15-that was absent in females. Our results suggest that sex differences may be a factor in sustaining WNV immunity.

  View details for DOI 10.1093/femspd/ftz016

  View details for PubMedID 30915442

  View details for PubMedCentralID PMC6465207

• P2X Antagonists Inhibit HIV-1 Productive Infection and Inflammatory Cytokines Interleukin-10 (IL-10) and IL-1β in a Human Tonsil Explant Model. Journal of virology Soare, A. Y., Durham, N. D., Gopal, R., Tweel, B., Hoffman, K. W., Brown, J. A., O'Brien, M., Bhardwaj, N., Lim, J. K., Chen, B. K., Swartz, T. H. 2019; 93 (1)

  Abstract

  HIV-1 causes a persistent infection of the immune system that is associated with chronic comorbidities. The mechanisms that underlie this inflammation are poorly understood. Emerging literature has implicated proinflammatory purinergic receptors and downstream signaling mediators in HIV-1 infection. This study probed whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. An ex vivo human tonsil histoculture infection model was developed to support HIV-1 productive infection and stimulated the inflammatory cytokine interleukin-1 beta (IL-1β) and the immunosuppressive cytokine interleukin-10 (IL-10). This study tests whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. The purinergic P2X1 receptor antagonist NF449, the purinergic P2X7 receptor antagonist A438079, and azidothymidine (AZT) were tested in HIV-1-infected human tonsil explants to compare levels of inhibition of HIV-1 infection and HIV-stimulated inflammatory cytokine production. All drugs limited HIV-1 productive infection, but P2X-selective antagonists (NF449 and A438079) significantly lowered HIV-stimulated IL-10 and IL-1β. We further observed that P2X1- and P2X7-selective antagonists can act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Our findings highlight the differential effects of HIV-1 on inflammation in peripheral blood compared to those in lymphoid tissue. For the first time, we demonstrate that P2X-selective antagonists act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Drugs that block these pathways can have independent inhibitory activities against HIV-1 infection and HIV-induced inflammation.IMPORTANCE Patients who are chronically infected with HIV-1 experience sequelae related to chronic inflammation. The mechanisms of this inflammation have not been elucidated. Here, we describe a class of drugs that target the P2X proinflammatory signaling receptors in a human tonsil explant model. This model highlights differences in HIV-1 stimulation of lymphoid tissue inflammation and peripheral blood. These drugs serve to block both HIV-1 infection and production of IL-10 and IL-1β in lymphoid tissue, suggesting a novel approach to HIV-1 therapeutics in which both HIV-1 replication and inflammatory signaling are simultaneously targeted.

  View details for DOI 10.1128/JVI.01186-18

  View details for PubMedID 30305360

  View details for PubMedCentralID PMC6288349

• The homozygous CX3CR1-M280 mutation impairs human monocyte survival. JCI insight Collar, A. L., Swamydas, M., O'Hayre, M., Sajib, M. S., Hoffman, K. W., Singh, S. P., Mourad, A., Johnson, M. D., Ferre, E. M., Farber, J. M., Lim, J. K., Mikelis, C. M., Gutkind, J. S., Lionakis, M. S. 2018; 3 (3)

  Abstract

  Several reports have demonstrated that mouse Cx3cr1 signaling promotes monocyte/macrophage survival. In agreement, we previously found that, in a mouse model of systemic candidiasis, genetic deficiency of Cx3cr1 resulted in increased mortality and impaired tissue fungal clearance associated with decreased macrophage survival. We translated this finding by showing that the dysfunctional CX3CR1 variant CX3CR1-M280 was associated with increased risk and worse outcome of human systemic candidiasis. However, the impact of this mutation on human monocyte/macrophage survival is poorly understood. Herein, we hypothesized that CX3CR1-M280 impairs human monocyte survival. We identified WT (CX3CR1-WT/WT), CX3CR1-WT/M280 heterozygous, and CX3CR1-M280/M280 homozygous healthy donors of European descent, and we show that CX3CL1 rescues serum starvation-induced cell death in CX3CR1-WT/WT and CX3CR1-WT/M280 but not in CX3CR1-M280/M280 monocytes. CX3CL1-induced survival of CX3CR1-WT/WT monocytes is mediated via AKT and ERK activation, which are both impaired in CX3CR1-M280/M280 monocytes, associated with decreased blood monocyte counts in CX3CR1-M280/M280 donors at steady state. Instead, CX3CR1-M280/M280 does not affect monocyte CX3CR1 surface expression or innate immune effector functions. Together, we show that homozygocity of the M280 polymorphism in CX3CR1 is a potentially novel population-based genetic factor that influences human monocyte signaling.

  View details for DOI 10.1172/jci.insight.95417

  View details for PubMedID 29415879

  View details for PubMedCentralID PMC5821174

• Alveolar macrophages are critical for broadly-reactive antibody-mediated protection against influenza A virus in mice. Nature communications He, W., Chen, C. J., Mullarkey, C. E., Hamilton, J. R., Wong, C. K., Leon, P. E., Uccellini, M. B., Chromikova, V., Henry, C., Hoffman, K. W., Lim, J. K., Wilson, P. C., Miller, M. S., Krammer, F., Palese, P., Tan, G. S. 2017; 8 (1): 846

  Abstract

  The aim of candidate universal influenza vaccines is to provide broad protection against influenza A and B viruses. Studies have demonstrated that broadly reactive antibodies require Fc-Fc gamma receptor interactions for optimal protection; however, the innate effector cells responsible for mediating this protection remain largely unknown. Here, we examine the roles of alveolar macrophages, natural killer cells, and neutrophils in antibody-mediated protection. We demonstrate that alveolar macrophages play a dominant role in conferring protection provided by both broadly neutralizing and non-neutralizing antibodies in mice. Our data also reveal the potential mechanisms by which alveolar macrophages mediate protection in vivo, namely antibody-induced inflammation and antibody-dependent cellular phagocytosis. This study highlights the importance of innate effector cells in establishing a broad-spectrum antiviral state, as well as providing a better understanding of how multiple arms of the immune system cooperate to achieve an optimal antiviral response following influenza virus infection or immunization.Broadly reactive antibodies that recognize influenza A virus HA can be protective, but the mechanism is not completely understood. Here, He et al. show that the inflammatory response and phagocytosis mediated by the interaction between protective antibodies and macrophages are essential for protection.

  View details for DOI 10.1038/s41467-017-00928-3

  View details for PubMedID 29018261

  View details for PubMedCentralID PMC5635038

• Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis. Journal of virology Bardina, S. V., Brown, J. A., Michlmayr, D., Hoffman, K. W., Sum, J., Pletnev, A. G., Lira, S. A., Lim, J. K. 2017; 91 (10)

  Abstract

  West Nile virus (WNV) is a mosquito-transmitted flavivirus that can cause debilitating encephalitis. To delineate the mechanisms behind this pathology, we studied Ccr7-deficient mice, which afforded us the capacity to study infection in mice with disrupted peripheral cellular trafficking events. The loss of Ccr7 resulted in an immediate pan-leukocytosis that remained elevated throughout the infection. This leukocytosis resulted in a significant enhancement of leukocyte accumulation within the central nervous system (CNS). Despite an excess of virus-specific T cells in the CNS, Ccr7-deficient mice had significantly higher CNS viral loads and mortality rates than wild-type animals. Mechanistically, the elevated trafficking of infected myeloid cells into the brain in Ccr7-deficient mice resulted in increased levels of WNV in the CNS, thereby effectively contributing to neuroinflammation and lowering viral clearance. Combined, our experiments suggest that during WNV infection, Ccr7 is a gatekeeper for nonspecific viral transference to the brain.IMPORTANCE In this study, we show that Ccr7 is required for the sufficient migration of dendritic cells and T cells into the draining lymph node immediately following infection and for the restriction of leukocyte migration into the brain. Further, the severe loss of dendritic cells in the draining lymph node had no impact on viral replication in this organ, suggesting that WNV may migrate from the skin into the lymph node through another mechanism. Most importantly, we found that the loss of Ccr7 results in a significant leukocytosis, leading to hypercellularity within the CNS, where monocytes/macrophages contribute to CNS viremia, neuroinflammation, and increased mortality. Together, our data point to Ccr7 as a critical host defense restriction factor limiting neuroinflammation during acute viral infection.

  View details for DOI 10.1128/JVI.02409-16

  View details for PubMedID 28356527

  View details for PubMedCentralID PMC5411599

• Extrapulmonary Aspergillus infection in patients with CARD9 deficiency. JCI insight Rieber, N., Gazendam, R. P., Freeman, A. F., Hsu, A. P., Collar, A. L., Sugui, J. A., Drummond, R. A., Rongkavilit, C., Hoffman, K., Henderson, C., Clark, L., Mezger, M., Swamydas, M., Engeholm, M., Schüle, R., Neumayer, B., Ebel, F., Mikelis, C. M., Pittaluga, S., Prasad, V. K., Singh, A., Milner, J. D., Williams, K. W., Lim, J. K., Kwon-Chung, K. J., Holland, S. M., Hartl, D., Kuijpers, T. W., Lionakis, M. S. 2016; 1 (17): e89890

  Abstract

  Invasive pulmonary aspergillosis is a life-threatening mycosis that only affects patients with immunosuppression, chemotherapy-induced neutropenia, transplantation, or congenital immunodeficiency. We studied the clinical, genetic, histological, and immunological features of 2 unrelated patients without known immunodeficiency who developed extrapulmonary invasive aspergillosis at the ages of 8 and 18. One patient died at age 12 with progressive intra-abdominal aspergillosis. The other patient had presented with intra-abdominal candidiasis at age 9, and developed central nervous system aspergillosis at age 18 and intra-abdominal aspergillosis at age 25. Neither patient developed Aspergillus infection of the lungs. One patient had homozygous M1I CARD9 (caspase recruitment domain family member 9) mutation, while the other had homozygous Q295X CARD9 mutation; both patients lacked CARD9 protein expression. The patients had normal monocyte and Th17 cell numbers in peripheral blood, but their mononuclear cells exhibited impaired production of proinflammatory cytokines upon fungus-specific stimulation. Neutrophil phagocytosis, killing, and oxidative burst against Aspergillus fumigatus were intact, but neither patient accumulated neutrophils in infected tissue despite normal neutrophil numbers in peripheral blood. The neutrophil tissue accumulation defect was not caused by defective neutrophil-intrinsic chemotaxis, indicating that production of neutrophil chemoattractants in extrapulmonary tissue is impaired in CARD9 deficiency. Taken together, our results show that CARD9 deficiency is the first known inherited or acquired condition that predisposes to extrapulmonary Aspergillus infection with sparing of the lungs, associated with impaired neutrophil recruitment to the site of infection.

  View details for DOI 10.1172/jci.insight.89890

  View details for PubMedID 27777981

  View details for PubMedCentralID PMC5070961

• Batf3-dependent CD103(+) dendritic cell accumulation is dispensable for mucosal and systemic antifungal host defense. Virulence Break, T. J., Hoffman, K. W., Swamydas, M., Lee, C. R., Lim, J. K., Lionakis, M. S. 2016; 7 (7): 826-35

  Abstract

  Dendritic cells (DCs) are critical for defense against a variety of pathogens and the formation of adaptive immune responses. The transcription factor Batf3 is critical for the development of CD103(+)CD11b(-) DCs, which promote IL-12-dependent protective immunity during viral and parasitic infections, dampen Th2 immunity during helminthic infection, and exert detrimental effects during bacterial infection. Whether CD103(+) DCs modulate immunity during systemic or mucosal fungal disease remains unknown. Herein, we report that Batf3 is critical for accumulation of CD103(+) DCs in the kidney and tongue at steady state, for their expansion during systemic and oropharyngeal candidiasis, and for tissue-specific production of IL-12 in kidney but not tongue during systemic and oropharyngeal candidiasis, respectively. Importantly, deficiency of CD103(+) DCs does not impair survival or fungal clearance during systemic or oropharyngeal candidiasis, indicating that Batf3-dependent CD103(+) DC accumulation mediates pathogen- and tissue-specific immune effects.

  View details for DOI 10.1080/21505594.2016.1186324

  View details for PubMedID 27191829

  View details for PubMedCentralID PMC5029292

• Differences in Early Cytokine Production Are Associated With Development of a Greater Number of Symptoms Following West Nile Virus Infection. The Journal of infectious diseases Hoffman, K. W., Sachs, D., Bardina, S. V., Michlmayr, D., Rodriguez, C. A., Sum, J., Foster, G. A., Krysztof, D., Stramer, S. L., Lim, J. K. 2016; 214 (4): 634-43

  Abstract

  West Nile virus (WNV) is an emerging cause of meningitis and encephalitis in the United States. Although severe neuroinvasive disease and death can occur in rare instances, the majority of infected individuals remain asymptomatic or present with a range of clinical manifestations associated with West Nile fever.To better understand the interindividual variability associated with the majority of WNV infections, we evaluated the association of cytokine/chemokine production and outcome of infection among 115 WNV-positive US blood donors identified in 2008-2011. All subjects self-reported symptoms as having occurred during the 2 weeks following blood donation, using a standardized questionnaire.We discovered that, prior to seroconversion, an early potent, largely type I interferon-mediated response correlated with development of a greater number of symptoms in WNV-infected individuals. Interestingly, individuals who developed fewer symptoms had not only a more modest type I interferon response initially, but also a protracted cytokine response after seroconversion, marked by the production of monocyte and T-cell-associated chemokines.Collectively, our data suggest that, although an early type I interferon response appears to be crucial to control WNV infection, successful immunity may require a modest early response that is maintained during the course of infection.

  View details for DOI 10.1093/infdis/jiw179

  View details for PubMedID 27142077

  View details for PubMedCentralID PMC4957436

• Differential Roles of Chemokines CCL2 and CCL7 in Monocytosis and Leukocyte Migration during West Nile Virus Infection. Journal of immunology (Baltimore, Md. : 1950) Bardina, S. V., Michlmayr, D., Hoffman, K. W., Obara, C. J., Sum, J., Charo, I. F., Lu, W., Pletnev, A. G., Lim, J. K. 2015; 195 (9): 4306-18

  Abstract

  West Nile virus (WNV) is a re-emerging pathogen and the leading cause of epidemic encephalitis in the United States. Inflammatory monocytes are a critical component of the cellular infiltrate found in the CNS during WNV encephalitis, although the molecular cues involved in their migration are not fully understood. In mice, we previously showed that WNV infection induces a CCR2-dependent monocytosis that precedes monocyte migration into the CNS. Currently, the relative contribution of the CCR2 ligands, chemokines CCL2 and CCL7, in directing monocyte mobilization and leukocyte migration into the CNS is unclear. In this study, we demonstrate that, although both CCL2 and CCL7 are required for efficient monocytosis and monocyte accumulation in the CNS, only CCL7 deficiency resulted in increased viral burden in the brain and enhanced mortality. The enhanced susceptibility in the absence of CCL7 was associated with the delayed migration of neutrophils and CD8(+) T cells into the CNS compared with WT or Ccl2(-/-) mice. To determine whether CCL7 reconstitution could therapeutically alter the survival outcome of WNV infection, we administered exogenous CCL7 i.v. to WNV-infected Ccl7(-/-) mice and observed a significant increase in monocytes and neutrophils, but not CD8(+) T cells, within the CNS, as well as an enhancement in survival compared with Ccl7(-/-) mice treated with a linear CCL7 control peptide. Our experiments suggest that CCL7 is an important protective signal involved in leukocyte trafficking during WNV infection, and it may have therapeutic potential for the treatment of acute viral infections of the CNS.

  View details for DOI 10.4049/jimmunol.1500352

  View details for PubMedID 26401006

  View details for PubMedCentralID PMC4610864

• Dynamic asymmetry and the role of the conserved active-site thiol in rabbit muscle creatine kinase. Biochemistry Londergan, C. H., Baskin, R., Bischak, C. G., Hoffman, K. W., Snead, D. M., Reynoso, C. 2015; 54 (1): 83-95

  Abstract

  Symmetric and asymmetric crystal structures of the apo and transition state analogue forms, respectively, of the dimeric rabbit muscle creatine kinase have invoked an "induced fit" explanation for asymmetry between the two subunits and their active sites. However, previously reported thiol reactivity studies at the dual active-site cysteine 283 residues suggest a more latent asymmetry between the two subunits. The role of that highly conserved active-site cysteine has also not been clearly determined. In this work, the S-H vibrations of Cys283 were observed in the unmodified MM isoform enzyme via Raman scattering, and then one and both Cys283 residues in the same dimeric enzyme were modified to covalently attach a cyano group that reports on the active-site environment via its infrared CN stretching absorption band while maintaining the catalytic activity of the enzyme. Unmodified and Cys283-modified enzymes were investigated in the apo and transition state analogue forms of the enzyme. The narrow and invariant S-H vibrational bands report a homogeneous environment for the unmodified active-site cysteines, indicating that their thiols are hydrogen bonded to the same H-bond acceptor in the presence and absence of the substrate. The S-H peak persists at all physiologically relevant pH's, indicating that Cys283 is protonated at all pH's relevant to enzymatic activity. Molecular dynamics simulations identify the S-H hydrogen bond acceptor as a single, long-resident water molecule and suggest that the role of the conserved yet catalytically unnecessary thiol may be to dynamically rigidify that part of the active site through specific H-bonding to water. The asymmetric and broad CN stretching bands from the CN-modified Cys283 suggest an asymmetric structure in the apo form of the enzyme in which there is a dynamic exchange between spectral subpopulations associated with water-exposed and water-excluded probe environments. Molecular dynamics simulations indicate a homogeneous orientation of the SCN probe group in the active site and thus rule out a local conformational explanation at the residue level for the multipopulation CN stretching bands. The homogeneous simulated SCN orientation suggests strongly that a more global asymmetry between the two subunits is the cause of the CN probe's broad and asymmetric infrared line shape. Together, these spectral observations localized at the active-site cysteines indicate an intrinsic, dynamic asymmetry between the two subunits that exists already in the apo form of the dimeric creatine kinase enzyme, rather than being induced by the substrate. Biochemical and methodological consequences of these conclusions are considered.

  View details for DOI 10.1021/bi5008063

  View details for PubMedID 25347386

• A new Raman spectroscopic probe of both the protonation state and noncovalent interactions of histidine residues. The journal of physical chemistry. A Hoffman, K. W., Romei, M. G., Londergan, C. H. 2013; 117 (29): 5987-96

  Abstract

  The amino acid histidine (His) has a number of unique roles that can dictate function in proteins, and these roles are typically conferred through noncovalent interactions that depend on the protonation state of His's 4-substituted imidazole ring. His's protonation state can vary near physiological pH, and a probe of His's variable protonation state and its resulting noncovalent interactions that has both high time resolution and no sample limitations could find wide use in determining the role of particular His residues in proteins. Here we use a classic deuterium exchange reaction to replace the C2-H hydrogen atom of the His imidazole ring with deuterium, leading to a unique aromatic C2-D stretching vibration whose frequency is sensitive to environmental changes across the entire imidazole ring. Using nonresonant Raman spectroscopy, we demonstrate using model compounds that the frequency of this C2-D vibration shifts by 35 cm(-1) upon changes in the His protonation state. The C2-D band is a very weak infrared absorber, so this vibration is not expected to be useful in infrared transmission experiments for proteins. Solvent-dependent Raman experiments indicate that the C2-D band of the neutral imidazole ring is sensitive to H-bonding interaction with donors and acceptors of varying strengths, suggesting that the C2-D frequency can be used to identify H-bonding partners of specific His residues. Raman spectra at varying concentrations of Cu(2+) also show the C2-D band's sensitivity to metal coordination, with differences due to changes in the coordination environment. The strong Raman signal of this band and the sampling flexibility of Raman spectroscopy suggest that this vibration could be very useful in documenting the local role of His residues in many His-containing proteins and protein assemblies.

  View details for DOI 10.1021/jp311815k

  View details for PubMedID 23451758